Method and apparatus for the setting or adjustment of a cardiac pacemaker

ABSTRACT

A method of setting or adjusting a cardiac pacemaker in a patient diagnosed with cardiac asynchrony, which method comprises the steps of: i) implanting cardiac pacing wires into at least the right ventricle and the left ventricle of the heart of the patient, ii) continuously monitoring and recording the cardiac output, nominal stroke volume and/or arterial pressure of the patient on a beat-by-beat basis, iii) continuously monitoring and recording the respiratory cycle of the patient, and iv) adjusting the conduction delay between the electronic impulses to the cardiac pacing wires until a synchronization of respiratory changes with changes in the cardiac output, stroke volume or arterial pressure of the patient is obtained.

The present invention relates to a method and apparatus for the settingor adjustment of a cardiac pacemaker and, in particular, to the settingor adjustment of a cardiac pacemaker in a patient diagnosed withasynchrony.

Cardiac heart failure is a syndrome which is associated with ill healthand death, despite continuing advances in drug therapy. It has beenfound that many congestive heart failure (CHF) patients have a commonpathology whereby the left ventricle (the side which supplies blood tothe body) is not contracting in synchrony with the other chambers of theheart. For example, it may contract during left atrial filling and/orafter right ventricular diastole begins. This can lead to reduced leftventricular filling and mitral valve regurgitation. These patientsusually have an increase in blood pressure(s) on the left side of theheart, with the resulting progressive distension of the left ventriclewall, consequent failing left heart performance and ultimately death.

Standard dual chamber pacemakers which pace and synchronise the rightatrium and the right ventricle do not appear to improve the condition ofpatients with New York Heart Association (NHYA) Class III and Class IVheart failure—they are not therefore of use in the management of CHF. Ithas been thought that the efficacy of the heart in CHF patients could beincreased or restored if the start of the ventricular systole could besynchronised by pacing the right atrium of the heart followed by theright ventricle and left ventricle. This technique is known asbiventricular pacing, or resynchronisation therapy. However, from thevarious studies which have been carried out it is clear that while somepatients respond remarkably, for many patients there is no significantimprovement. Studies in respect of biventricular pacing in congestiveheart failure patients are described in, for example, Morris Thurgood,J. A. and Frenneaux, M. P.; Pacing in Congestive Heart Failure, CurrentControlled Trials in Cardiovascular Medicine 2000; 1(2): 107-114 andHaywood, G; Biventricular pacing in heart failure: update on resultsfrom clinical trials, Current. Controlled Trials in CardiovascularMedicine 2001; 2(6): 292-297.

It is clear that considerable uncertainty exists as to how exactlybiventricular pacing actually works, which CHF patients will respond andwhether the benefits of biventricular pacing are better than leftventricular pacing only. One problem is that the restoration ofsynchrony of the left and right ventricles of the heart is verydifficult to demonstrate clinically in the catheterisation laboratory.Early studies used echocardiography and radionucleotideangioscintigraphy (radioactivity injection into the heart with theventricle being subsequently visualised by use of a gamma camera.) Thesetechniques are complex, invasive and costly. Equally blood flowmeasurements with a thermodilution (bolus or continuous) catheter and/orDoppler ultrasound are also invasive and limited in terms of adequatelydemonstrating the restoration of normal cardiac physiology. Finally,resolution of small and possibly not persistent, changes in blood flowdemand a non or minimally invasive monitoring system with the ability toresolve small (<2%) real time changes in stroke volume.

It has therefore previously been very difficult to ascertain whether ornot fitting a biventricular cardiac pacemaker to a CHF patient actuallyimproves the cardiac function.

Furthermore, the clinician is not only trying to restore cardiacsynchrony but to optimise the left ventricle response to preload, i.e.to set the heart rate and conductive delays of the pacemaker wires thatallow for the most efficient provision of both normal and demandresponsive systemic tissue oxygen delivery.

The extent to which the ventricle is filled pre the systolic contractioninfluences the ejected volume (stroke volume) of that beat (Starlingmechanism.) Essentially, the more the ventricle is filled before thecontraction phase, the more work is done ejecting blood by thatcontraction. This is true i.e. there is a linear relationship only up toa certain maximum filling pressure at which the ventricle becomes lessresponsive. Changes in the intra thoracic pressure in positive pressureventilated patients cause changes to the filling pressure of the leftventricle which, through the Starling mechanism, results in differingpre systolic left ventricular end diastolic volume. This results insmall (but measurable by arterial waveform analysis) respiratory drivencyclical changes in the ejected stroke volume. The magnitude of thestroke volume variation cross the respiratory cycle and/or the resultantarterial pulse pressure (pulse pressure variation %—PPV %) are usefulparameters and are known to accurately predict the likely response ofthe left ventricle to additional fluid administration in positivepressure ventilated patients.

Therefore the magnitude of respiratory induced blood flow and pressurechanges can be used to predict the likely response to increased venousreturn. Clinically this technique is mostly used in mechanicallyventilated critical care patients in conjunction with stroke volume andcardiac output measurements to optimise the cardiovascular status of thepatient.

Less well known is that in spontaneously breathing patients without CHFcyclical changes in these parameters is also exhibited. Thus, duringinspiration (breathing in) the diaphragm of the patient moves down,thereby decreasing the intra thoracic pressure and increasing the venousfilling and stroke volume of the heart. During expiration (breathingout) the diaphragm of the patient moves up, thereby increasing the intrathoracic pressure and decreasing the venous filling and stroke volume ofthe heart. In spontaneously breathing patients with CHF this normalphysiological pattern is not generally displayed. We have now realisedthat advantage could be taken of the changes of stroke volume orarterial pulse pressure across the respiratory cycle in order todetermine whether or not a CHF patient is responding to the insertionand setting of a cardiac pacemaker in the heart.

Accordingly, the present invention provides a method of setting oradjusting a cardiac pacemaker in a patient diagnosed with cardiacasynchrony, which method comprises he steps of:

-   -   i) implanting cardiac pacing wires into at least the right        ventricle and the left ventricle of the heart of the patient,    -   ii) continuously monitoring and recording the cardiac output,        nominal stroke volume and/or arterial pressure of the patient on        a beat-by-beat basis,    -   iii) continuously monitoring and recording the respiratory cycle        of the patient, and    -   iv) adjusting the conduction delay between the electronic        impulses to the cardiac pacing wires until a synchronization of        respiratory changes with changes in the cardiac output, stroke        volume or arterial pressure of the patient is obtained.

In carrying out the present invention, the respiratory cycle of thepatient can be recorded visually, or preferably by means of computeranalysis of the arterial waveform, or by means of a strain gauge placedaround the patient's chest.

The nominal stroke volume may be obtained using an adaptation of themethod described in WO 97/24982 or WO 99102086 for measuring cardiacoutput in a patient. In both of these methods the nominal stroke volumeis calculated and the cardiac output obtained by multiplying the strokevolume by the heart rate.

The nominal stroke volume is uncalibrated data and may be converted intocalibrated data, if desired, by multiplying the nominal stroke volume bya calibration actor to give the true stroke volume.

Accordingly, in a first aspect of the present invention the nominalstroke volume may be obtained by a method which comprises the steps of:

-   -   (a) recording and storing the arterial blood pressure waveform        of a patient from a blood pressure monitoring device over a        period of time;    -   (b) subjecting the waveform obtained in step (a) to a non-linear        transformation that corrects for the variation of the        characteristics of the arterial system with pressure;    -   (c) subjecting the corrected waveform from step (b) to        autocorrelation in order to derive the pulsatility and heart        rate of the corrected waveform; and    -   (d) calculating the nominal stroke volume from the pulsatility.

In a second aspect of the present invention the nominal stroke volumemay be obtained by a method which comprises the steps of:

-   -   (e) recording and storing the arterial blood pressure waveform        of a patient from a blood pressure monitoring device over a        period of time;    -   (f) subtracting the mean of the waveform from step (e) and        subjecting the data so obtained to autocorrelation;    -   (g) transforming the data from step (f) into data which relates        to the pulsatility and heart rate of the waveform; and    -   (h) calculating the nominal stroke volume from the pulsatility.

In a third aspect of the present invention the nominal stroke volume maybe obtained by a method which comprises the steps of:

-   -   (i) recording and storing the arterial blood pressure waveform        of a patient from a blood pressure monitoring device over a        period of time;    -   (j) subjecting the data obtained in step (i) to Fourier analysis        in order to obtain the modulus of the first harmonic; and    -   (k) determining the nominal stroke volume from the modulus of        the first harmonic obtained in step (j) and data relating to the        arterial blood pressure and the heart rate.

In a fourth aspect of the present invention the nominal stroke volumemay be obtained by a method which comprises the steps of:

-   -   (l) recording and storing the arterial blood pressure waveform        of a patient from a blood pressure monitoring device over a        period of time;    -   (m) subjecting the waveform obtained in step (l) to a non-linear        transformation that corrects for the variation of the        characteristics of the arterial system with pressure;    -   (n) subjecting the data obtained in step (m) to Fourier analysis        in order to obtain the modulus of the first harmonic;    -   (o) determining the nominal stroke volume from the modulus of        the first harmonic obtained in step (n) and data relating to the        heart rate and optionally the arterial blood pressure.

In the first and fourth methods for obtaining the nominal stroke volumethe pressure waveform is preferably transformed via a “look up” curve,with the mean of the data then being found and subtracted, into datawhich represents the pressure/volume relationship of the arterialsystem. The basic approximation to a look up table is known in the artand the relationship is non-linear, a series of such curves beingdescribed in Remington et al, 1948, Am. J. Physiol 153: 298-308: Volumeelasticity characteristics of the human aorta and prediction of thestroke volume from the pressure pulse.

In the first method for obtaining the nominal stroke volume, thecorrected waveform from step (b) is subjected to autocorrelation inorder to determine the pulsatility and heart rate of the transformedwaveform. Autocorrelation is defined in Dictionary of Science andTechnology, Academic Press, 1992, p 186. The technique ofautocorrelation is known in the art and is further described in detailin WO 97/24982.

In the second method for obtaining the nominal stroke volume, theautocorrelation is carried out on the arterial blood pressure data aftersubtraction of the mean of the waveform. The autocorrelation data isthen transformed into data which relates to the pulsatility and heartrate of the waveform.

In the third and fourth methods for obtaining the stroke volume thearterial blood pressure waveform of the patient, which may be subjectedto a non-linear transformation that corrects for the variation of thecharacteristics of the arterial system with pressure, is subjected to aFourier analysis in order to obtain the modulus of the first harmonic.Fourier analysis is known in the art and may be used to determine theharmonic components of a complex name and is described in detail in manymathematical and physics textbooks. Fourier analysis is also describedin more detail in WO 99/02086.

In carrying out the various methods for obtaining the nominal strokevolume the patient's arterial blood pressure is monitored continuouslyby conventional means from, for example, the aorta, the brachial arteryor radial artery. Accordingly, the patient's arterial blood pressure maybe monitored using an arterial catheter with a transducer system or anon-invasive method. The output from the pressure measuring deviceprovides the blood pressure over a period of time.

It will be understood that in carrying out the method of the presentinvention the changes in the arterial pressure may be monitored insteadof the changes in the stroke volume and used to indicate when there is asynchronization between the respiratory cycle and heart function. Thesystolic or diastolic pressures may be monitored or preferably thearterial pulse pressure (systolic pressure minus diastolic pressure) ismonitored.

Preferably in carrying out the present invention a third cardiac pacingwire is additionally implanted into the right atrium of the patient'sheart.

The adjustment of the conduction delays between the individualelectronic impulses to the different cardiac pacing wires may beadjusted systematically using a pre-determined matrix. As the conductiondelays are varied, the changes of cardiac output, stroke volume orarterial pressure are monitored and recorded. The conduction delays maybe varied until a sufficient asynchrony of the heart is obtained suchthat there are observable respiratory derived changes in cardiac output,stroke volume and/or arterial pressure.

The method of the present invention also includes the possibility of thepacing rate of the electronic impulses to the cardiac pacing wires beingvaried. For example the pacing rate may be varied between 40 and 100beats per minute, preferably between 80 and 100 beats per minute.

In carrying out the method of the present invention the cardiac output,nominal stroke volume and/or arterial pressure and the respiratory cycleof the patient will preferably be recorded and stored in anappropriately programmed computer and displayed upon a display deviceintegral with, or connected to, the computer. A cardiovascularmonitoring device that uses the radial arterial waveform to derive andstore real time blood pressure, cardiac output and stroke volume data isthe PulseCo System available from LiDCO Ltd., London, United Kingdom.This device can be modified so as to simultaneously record and storeinformation in respect of the respiratory cycle of the patient. With thereal time respiratory cycle data superimposed upon the same displayscreen as the real time information in relation to blood pressure,cardiac output and stroke volume, it is easy to see when there issynchronization of the changes in nominal stroke volume or arterialpressure over time with the respiratory cycle.

The general theory upon which the present invention is predicated mayalso be used to adjust cardiac pacemakers which are already implantedinto a subject's heart in order to improve or adjust the settingsthereof.

Accordingly, in a still further aspect the present invention provides amethod of adjusting a cardiac pacemaker having cardiac pacing wiresimplanted into at least the right ventricle and the left ventricle ofthe heart of a subject, which method comprises the steps of:

-   -   (x) continuously monitoring and recording the cardiac output,        nominal stroke volume and/or arterial pressure of the subject on        a beat-by-beat basis,    -   (xi) continuously monitoring and recording the respiratory cycle        of the patient, and    -   (xii) adjusting the conduction delay between the electronic        impulses to the cardiac pacing wires until a synchronization of        respiratory changes with changes in the cardiac output, stroke        volume or arterial pressure of the subject is obtained.

The manner in which the previously implanted pacemakers may be adjustedfollows the general teaching above in relation to the settings oradjustment of cardiac pacemakers in a patient diagnosed with asynchrony.

The present invention also includes within its scope an apparatus forsetting or adjusting a cardiac pacemaker in a patient diagnosed withasynchrony and having cardiac pacing wires implanted into at least theright ventricle and the left ventricle, which apparatus comprises:

-   -   (A) means for continuously monitoring and recording the cardiac        output, nominal stroke volume and/or arterial pressure of the        patient;    -   (B) means for continuously monitoring and recording the        respiratory cycle of the patient;    -   (C) means for adjusting the delay between the electronic        impulses to the pacing wires; and    -   (D) means for determining when a synchronization of the        respiratory changes with changes in the cardiac output, stroke        volume or arterial pressure is obtained.

The method of the present invention not only enables the clinician toselect appropriate settings for a cardiac pacemaker to reduce asynchronyor restore synchrony in a patient, but also to select settings for theparticular patient which optimise cardiac output and oxygen delivery.

Furthermore, when synchrony of the left ventricle has been restored thesubsequent determination of changes in cardiac output, stroke volume orarterial pressure can be used as indicators of pre-load responsiveness.These changes can be observed by measuring the respiratory driven beatto beat changes of cardiac output, stroke volume and/or arterialpressure. The present invention is further described by reference to theaccompanying drawings, in which:

FIG. 1 illustrates the Frank-Starling's curve which plots stroke volumeagainst preload (in arbitrary units;

FIG. 2 illustrates for the patient of the Example the lack ofcorrelation in the respiratory cycle with changes in stroke volume andthe pulse pressure before activation of the pacemaker; and

FIG. 3 illustrates for the patient of the Example the correlation in therespiratory cycle with changes in pulse pressure and stroke volume withthe pacemaker activated at a heart rate of 80 beats per minute and anatrium to ventricle delay of 80 msec.

Referring to FIG. 1, the best pacemaker settings can be chosen so as tomaintain an appropriate cardiac output whilst keeping the patient on themost vertical portion of the ventricular Starling curve as illustrated.Thus, the heart rate and conduction delays of the electronic impulses tothe individual pacing wires can be chosen so as to provide the mostefficient (least work) forward blood flow.

The potential clinical application of the present invention include:

-   -   Improved patient screening for biventricular pacing        suitability—if following the implantation of the pacemaker leads        respiratory variations cannot be shown the ventricle may not be        capable of responding to this therapy and the cost of the pacer        can be avoided.    -   Epicardial lead placement optimisation—placement of the        pacemaker leads may be further optimised by this technique.    -   Optimisation of pacer settings in terms of time taken to        demonstrate resynchronisation, appropriate heart rate and        various chamber delays and ventricle pre load responsiveness.    -   Following setting of the pacemaker, appropriate feedback during        a stress and/or exercise test may be obtained in order that the        pacemaker settings may be optimised.    -   The present invention will be further described with reference        to the following Example.

EXAMPLE

A Clinical Example of the Use of Respiratory Driven Changes inHaemodynamic Parameters as a Predictor of Ventricle Synchrony and PreLoad Responsiveness

A male patient age 57 with NYHA Class III chronic heart failure and wasimplanted with a biventricular pacer for the improvement of hisasynchrony. The setting of the pacer was monitored with use of acardiovascular monitoring device (Pulse Co System—LiDCO Ltd, London, UK)that uses the radial arterial pressure waveform to derive and store realtime blood pressure, cardiac output and stroke volume data. The pacerwas a Guidant biventricular pacer in which the left and rightventricular wires are physically joined together and thereforeelectronic impulses to the right ventricle and left ventricle occur atthe same time and cannot be varied.

FIG. 2 illustrates the lack of correlation of the patient's respiratorycycle with the changes in stroke volume and pulse pressure before theactivation of the pacemaker.

FIG. 3 illustrates the correlation of the respiratory changes inarterial pulse pressure and stroke volume in this patient with thepacemaker being activated at a heart rate of 80 beats per minute andwith an atrium to ventricle delay of 80 msec.

Various atrium to ventricle conduction delays were applied to thispatient at two different heart rates and the results are given in Table1 below: Atrium to Ventricle Delay (msec) at 80 bpm Pacer 40 80 100 110120 150 off Cardiac 5.4 5.8 5.8 5.9 6 6 5.6 Output (1/min) Stroke 67.572.5 72.5 73.75 75 75 75 Volume (ml) Stroke 11 11 11 10 10 11 N/a VolumeVariation (%) Atrium to Ventricle Delay (msec) at 90 bpm Pacer 40 80 100110 Off Cardiac N/a 6.7 7 7.2 5.6 Output (1/min) Stroke N/a 74.44 77.7880.00 75 Volume (ml) Stroke N/a 9 6 5 N/a Volume Variation (%)

Stroke volume is the cardiac output divided by the heart rate. Thestroke volume variation % is (SV_(max)−SV_(min))/SV_(max)+SV_(min))%across the respiratory cycle. SVV % is regarded as a continuous preloadvariable and, in combination with continuously measured cardiac output,defined a number of important characteristics of cardiac functionfacilitating optional fluid management. In this patient his restingcardiac output was 5.6 1/min—which is normal for an adult male. So itwas assumed that his cardiac output was not low but he had very littlefunctional exercise reserve i.e. on exercise the increased venous returndid not produce a compensatory increase in stroke volume through theStarling mechanism. Thus even moderate exercise would lead to a rightheart to left heart imbalance (in effect right heart success) in bloodflow and dwelling of the blood on the post pulmonary left side of theheart. This would increase left arterial/ventricular filling pressuresand then result in the classical CHF clinical symptoms of pulmonaryoedema and breathlessness. The PulseCo System was able to show (via thecontinuous stroke volume and cardiac output traces) that thebiventricular pacer restored synchrony (defined as the appearance ofrespiratory variation in haemodynamic parameters) at all pacer settings.So in this patient a variety of settings were able to at least improveleft heart efficiency. In fact, this is not usually the case and in manyCHF biventricular patients synchrony is only seen at a few of therate/delay settings.

Therefore in this patient, as a variety of settings restored synchrony,the additional question to answer was which one of the settings was mostlikely to produce the required oxygen delivery whilst leaving theventricle with additional capacity to respond to further increases inpre load? The results demonstrate the following:

-   -   1. Increasing AV delay increased the cardiac output modestly at        both heart rates    -   2. Increasing the heart rate from 80 to 90 bpm increased cardiac        output more than the delay changes    -   3. With both the higher heart rate and with increasing AV delay        a reduction in pre load responsiveness, was observed—as assessed        by the decrease in the parameter of stroke volume variation from        11% (e.g. at 80 bpm & delay of 100 msec) to 5% (at 90 bpm & a        delay of 110 msec).    -   4. The conclusion was that this patient would have an adequate        cardiac output and a higher functional reserve i.e. potential        for response to the increased venous return associated with        exercise at 80 bpm and at a AV delay of between 80-120 msec. The        monitoring of beat to beat haemodynamic data allowed the choice        of both rate and AV delay.

1. A method of setting or adjusting a cardiac pacemaker in a patientdiagnosed with cardiac asynchrony, which method comprises the steps of:i) implanting cardiac pacing wires into at least the right ventricle andthe left ventricle of the heart of the patient, ii) continuouslymonitoring and recording the cardiac output, nominal stroke volumeand/or arterial pressure of the patient on a beat-by-beat basis, iii)continuously monitoring and recording the respiratory cycle of thepatient, and iv) adjusting the conduction delay between the electronicimpulses to the cardiac pacing wires until a synchronization ofrespiratory changes with changes in the cardiac output, stroke volume orarterial pressure of the patient is obtained.
 2. A method as claimed inclaim 1 wherein a cardiac pacing wire is additionally implanted into theright atrium of the patient's heart.
 3. A method as claimed in claim 1wherein the arterial pressure of the patient is monitored by means of anarterial line and a pressure transducer.
 4. A method as claimed in claim1 wherein the nominal stroke volume is derived by a method comprises thesteps of (a) recording and storing the arterial blood pressure waveformof a patient from a blood pressure monitoring device over a period oftime; (b) subjecting the waveform obtained in step (a) to a non-lineartransformation that corrects for the variation of the characteristics ofthe arterial system with pressure; (c) subjecting the corrected waveformfrom step (b) to autocorrelation in order to derive the pulsatility andheart rate of the corrected waveform; and (d) calculating the nominalstroke volume from the pulsatility.
 5. A method as claimed in claim 4wherein the transformation in step (b) is effected using a look up tablewith the mean of the date being found and substrated.
 6. A method asclaimed in claim 1 wherein the nominal stroke volume is derived by amethod which comprises the steps of: (e) recording and storing thearterial blood pressure waveform of a patient from a blood pressuremonitoring device over a period of time; (f) subtracting the mean of thewaveform from step (e) and subjecting the data so obtained toautocorrelation; (g) transforming the data from step (f) into data whichrelates to the pulsatility and heart rate of the waveform; and (h)calculating the nominal stroke volume from the pulsatility.
 7. A methodas claimed in claim 6 wherein the transformation in step (f) is effectedusing a look up table, with the mean of the data then being subtracted.8. A method as claimed in claim 1 wherein the nominal stroke volume isderived by a method which comprises the steps of: (i) recording andstoring the arterial blood pressure waveform of a patient from a bloodpressure monitoring device over a period of time; (j) subjecting thedata obtained in step (i) to Fourier analysis in order to obtain themodulus of the first harmonic; and (k) determining the nominal strokevolume from the modulus of the first harmonic obtained in step (j) anddata relating to the arterial blood pressure and the heart rate.
 9. Amethod as claimed in claim 1 wherein the nominal stroke volume isderived by a method which comprises the step of: (l) recording andstoring the arterial blood pressure waveform of a patient from a bloodpressure monitoring device over a period of time; (m) subjecting thewaveform obtained in step (I) to a non-linear transformation thatcorrects for the variation of the characteristics of the arterial systemwith pressure; (n) subjecting the data obtained in step (n) to Fourieranalysis in order to obtain the modulus of the first harmonic; (o)determining the nominal stroke volume from the modulus of the firstharmonic obtained in step (n) and data relating to the heart rate andoptionally the arterial blood pressure.
 10. A method as claimed in claim9 wherein the transformation in step (m) is effected using a look uptable, with the mean of the data then being subtracted.
 11. A method asclaimed in claim 1 wherein the respiratory cycle of the patient ismonitored by means of computer analysis of the arterial waveform, or bymeans of a strain gauge placed around the patient's chest.
 12. A methodas claimed in claim 1 wherein the conduction delay between theindividual electronic impulses to the different cardiac pacing wires isadjusted systematically using a predetermined matrix.
 13. A method asclaimed in claim 1 wherein the cardiac output, nominal stroke volumeand/or arterial pressure and the respiratory cycle of the patient arerecorded and stored in an appropriately programmed computer anddisplayed on a display device integral with or connected to thecomputer.
 14. A method as claimed in claim 1 wherein the pacing rate ofthe electronic impulses to the cardiac pacing wires may be varied.
 15. Amethod as claimed in claim 14 wherein the pacing rate is varied between80 and 100 beats per minute.
 16. A method of adjusting a cardiacpacemaker having cardiac pacing wires implanted into at least the rightventricle and the left ventricle of the heart of a subject, which methodcomprises the steps of: (x) continuously monitoring and recording thecardiac output, nominal stroke volume and/or arterial pressure of thesubject on a beat-by-beat basis, (xi) continuously monitoring andrecording the respiratory cycle of the patient, and (xii) adjusting theconduction delay between the electronic impulses to the cardiac pacingwires until a synchronization of respiratory changes with changes in thecardiac output, stroke volume or arterial pressure of the subject isobtained.
 17. A method as claimed in claim 16 wherein the cardiacpacemaker includes a cardiac pacing wire implanted into the right atriumof the subject's heart.
 18. (canceled)
 19. A method as claimed in claim16 where the respiratory cycle of the patient is monitored by means ofcomputer analysis of the arterial waveform, or by means of a straingauge placed around the patient's chest.
 20. A method as claimed inclaim 16 wherein the conduction delay between the individual electronicimpulses to the different cardiac pacing wires is adjustedsystematically using a pre-determined matrix.
 21. A method as claimed inclaim 16 wherein the cardiac output, nominal stroke volume and/orarterial pressure and the respiratory cycle of the patient are recordedand stored in an appropriately programmed computer and displayed on adisplay device integral with or connected to the computer.
 22. A methodas claimed in claim 16 wherein the pacing rate of the electronicimpulses to the cardiac pacing wires may be varied.
 23. A method asclaimed in claim 22 wherein the pacing rate is varied between 80 and 100beats per minute.
 24. A method as claimed in claim 1 wherein when asynchronization of respiratory changes with changes in the cardiacoutput, stroke volume or arterial pressure of the patient is obtained,the optimal setting of the pacemaker is then determined by monitoringthe stroke volume variation of the heart and selecting a pacemakersetting which provides an increased ventricle pre-load responsiveness.25. An apparatus for setting or adjusting a cardiac pacemaker in apatient diagnosed with asynchrony and having cardiac pacing wiresimplanted into at least the right ventricle and the left ventricle,which apparatus comprises: (A) means for continuously monitoring andrecording the cardiac output, nominal stroke volume and/or arterialpressure of the patient; (B) means for continuously monitoring andrecording the respiratory cycle of the patient; (C) means for adjustingthe delay between the electronic impulses to the pacing wires; and (D)means for determining when a synchronization of the respiratory changeswith changes in the cardiac output, stroke volume or arterial pressureis obtained.